There is a strong overlap between the substance abuse disorders and antisocial personality traits. This overlap may, even for a subgroup of substance abusers, be genetic. Since substantial evidence suggests that antisocial traits may be related to a low level of aversive arousal in the face of internally and externally imposed restraints on impulsive behavior, it may be that a subgroup of substance abusers share this tendency for low aversive arousal. Preliminary data suggest both that individuals with a history of substance abuse and subjects with antisocial traits show low levels of cerebrospinal phenylacetic acid (PAA). PAA is the primary metabolite of phenylethylamine, an endogenous amphetamine-like compound thought, in part, to mediate arousal. The purpose of this grant is to extend these findins to a large sample of male polydrug abusers using a gas chromatography/mass spectrometry analysis for levels of plasma PAA. Three studies involving 91 subjects wil be undertaken. Study 1 will compare 61 subjects with a history of polydrug abuse and/or personality disorder and 31 age-matched and sex-matched normal controls, predicting lowered plasma PAA in polydrug abusers and lowered plasma PAA correlated with antisocial- related personality disordered traits. Study 2 will test the correlation betwwen plasma and cerebrospinal fluid levels of PAA, as well as investigate the stress response of plasma PAA to the lumbar spinal tap in 25 of these subjects. Study 3 will assess the temporal reliability of plasma PAA levels in 41 subjects over a period of one week, and in 31 polydrug abusers at two months and four months into recovery during inpatient treatment. If plasma PAA proves to be a reliable trait marker for polydrug abusers with antisocial features, it may, in the long run, be useful in both longitudinal and genetic at risk studies. In addition, psychopharmacological interventions that raise levels of PAA, such as the MAO-B inhibitors, may potentially help compensate for this dysfunctional impulsivity.